Targeting the PEX Domain of MT1-MMP: Novel Cancer Therapy

靶向 MT1-MMP 的 PEX 结构域：新型癌症疗法

• 批准号: 7495931
• 负责人: Jian Cao
• 金额: $ 7.59万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7495931
• 关键词: 3-Dimensional; Adverse effects; Analytical Chemistry; Award; Base Sequence; Basement membrane; Behavior; Biological; Blood; Blood Vessels; CD44 Antigens; Cancer Model; Cancer Research Project; Carcinoma; Carcinoma in Situ; Catalytic Domain; Cell Adhesion Molecules; Cell Nucleus; Cell Proliferation; Cell Surface Proteins; Cell surface; Cell-Cell Adhesion; Cells; Cellular Morphology; Class; Cleaved cell; Collagen Type I; Complex; Computer Simulation; Data; Development; Diagnostic Neoplasm Staging; Dissection; Doctor of Medicine; E-Cadherin; Early treatment; Epithelial; Experimental Models; Extracellular Matrix; Extracellular Matrix Degradation; Figs - dietary; Fostering; Gel; Gene Expression Profile; Genetic Transcription; Goals; Grant; Growth; Hemopexin; In Situ; In Vitro; Interstitial Collagenase; Invasive; Lead; Loss of E-cadherin Expression; Lymph; Malignant Neoplasms; Malignant neoplasm of prostate; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Mesenchymal; Modeling; Mutagenesis; Neoplasm Metastasis; PHEX protein; Peptides; Pharmaceutical Preparations; Play; Process; Property; Prostatic Neoplasms; Protein Overexpression; Recombinant DNA; Recombinants; Research Personnel; Role; Safety; Signal Pathway; Specificity; Staging; Techniques; Tumor Cell Invasion; Tumor stage; base; cancer cell; cancer therapy; cell motility; chemokine; design; drug development; drug discovery; epithelial to mesenchymal transition; human MMP14 protein; in vivo; in vivo Model; inhibitor/antagonist; neoplastic cell; novel; prevent; proMMP-2; programs; three dimensional structure; tool; tumor progression

Epithelial-to-mesenchymal transition (EMT) has emerged as a critical step in the early stage of cancer. Better understanding of the mechanism of EMT will foster the development of inhibitors to prevent cancer progression. Considerable evidence has implicated membrane type 1-matrix metalloproteinase (MT1-MMP) in EMT and conversion to aggressive cancers. MT1-MMP activation of proMMP-2 and degradation of extracellular matrix (ECM) components are involved in cancer progression. MT1-MMP also cleaves numerous cell surface proteins, growth factors, and chemokines. We recently demonstrated that MT1-MMP: 1) cleaves E-cadherin at the cell-cell adherins junctions; 2) promotes cell migration/scattering in 3D type I collagen gels; 3) regulates cell proliferation in vitro and in vivo; and 5) changes cell morphology in 3D type I collagen gels. We also demonstrated that the hemopexin (PEX) domain of MT1-MMP plays a crucial role in cancer cell migration and pinpointed the regions required for MT1-MMP-mediated cell migration. Targeting the PEX domain with recombinant MT1-MMP PEX protein resulted in interference with MT1-MMP-induced cell migration. The primary goal of this grant is to define the involvement of the catalytic and non catalytic activities of MT1 -MMP in EMT. This characterizationwill facilitate our development of specific non-catalytic domain inhibitors of MT1-MMP that will be employed to interfere with cancer progression. To achieve this aim, the function of MT1-MMP in EMT in 3D cultured cancer cells will be examined. EMT-related transcription programs and signaling pathways will be evaluated. Based on a computational model of MT1-MMP and similarity with other MMPs, minimum motif(s) in the PEX domain of MT1-MMP required for cancer cell migration will be identified using a mutagenesis approach. Formation of homodimer and/or heterooligomer of MT1-MMP through PEX domain will be determined. Based on the identification of crucial PEX motifs, specific MT1-MMP inhibitory peptides will be designed and characterized using analytical chemistry and cell biological approaches. Functional inhibitory peptides will be produced and evaluated in an in vivo cancer model. The long-term goal is to develop a lead compound that will be modified to produce a MT1-MMP inhibitory drug with minimal side effects for treatment of cancer. I propose that the current project will help us to better understand cancer progression and lead to the development of novel basic tools for treatment of early stage cancer.

上皮间质转化（EMT）已成为癌症早期阶段的关键步骤。更好的 了解 EMT 机制将促进预防癌症抑制剂的开发 进展。大量证据表明膜 1 型基质金属蛋白酶 (MT1-MMP) 与 EMT 和转化为侵袭性癌症。 MT1-MMP 激活 proMMP-2 并降解 细胞外基质（ECM）成分参与癌症进展。 MT1-MMP 还可以裂解许多 细胞表面蛋白、生长因子和趋化因子。我们最近证明 MT1-MMP：1) 裂解 细胞-细胞粘附蛋白连接处的 E-钙粘蛋白； 2) 促进3D I型胶原蛋白凝胶中的细胞迁移/分散； 3）在体外和体内调节细胞增殖； 5) 改变 3D I 型胶原凝胶中的细胞形态。我们 还证明 MT1-MMP 的血红素结合蛋白 (PEX) 结构域在癌细胞迁移中起着至关重要的作用 并确定了 MT1-MMP 介导的细胞迁移所需的区域。定位 PEX 域 重组 MT1-MMP PEX 蛋白会干扰 MT1-MMP 诱导的细胞迁移。这 这笔赠款的主要目标是确定 MT1 -MMP 的催化和非催化活性在 急救人员。这种表征将有助于我们开发特定的非催化域抑制剂 MT1-MMP 将用于干扰癌症进展。为了实现这一目标，函数 将检查 3D 培养癌细胞中 EMT 中的 MT1-MMP。 EMT 相关转录程序和 将评估信号通路。基于MT1-MMP的计算模型以及与其他模型的相似性 将鉴定癌细胞迁移所需的 MMP、MT1-MMP PEX 结构域中的最小基序 使用诱变方法。通过 PEX 形成 MT1-MMP 的同二聚体和/或异寡聚体 域将被确定。基于关键 PEX 基序的识别，特异性 MT1-MMP 抑制 将使用分析化学和细胞生物学方法来设计和表征肽。 功能性抑制肽将在体内癌症模型中生产和评估。长期目标是 开发一种先导化合物，对其进行修饰以生产副作用最小的 MT1-MMP 抑制药物 达到治疗癌症的效果。我建议当前的项目将帮助我们更好地了解癌症 进展并导致开发治疗早期癌症的新型基本工具。